The present disclosure predominantly describes use of plungers and plunger assemblies according to the present invention in connection with pre-filled syringes. However, a skilled artisan would readily appreciate that the invention is not limited to pre-filled syringes, but may include other drug delivery devices, such as (pre-filled, filled before use, or empty) syringes, cartridges and auto-injectors.
Pre-filled parenteral containers, such as syringes or cartridges, are commonly prepared and sold so that the syringe does not need to be filled by the patient or caregiver before use. The syringe, and more specifically the barrel of the syringe, may be prefilled with a variety of different injection products, including, for example, saline solution, a dye for injection, or a pharmaceutically active preparation, among other items.
Pre-filled parenteral containers are typically sealed with a rubber plunger, which provides closure integrity over the shelf life of the container's contents. To use the prefilled syringe, the packaging and cap are removed, optionally a hypodermic needle or another delivery conduit is attached to the proximal end of the barrel, the delivery conduit or syringe is moved to a use position (such as by inserting it into a patient's blood vessel or into apparatus to be rinsed with the contents of the syringe), and the plunger is advanced in the barrel to inject contents of the barrel to the point of application.
Seals provided by rubber plungers in the barrel typically involve the rubber of the plunger being pressed against the barrel. Typically the rubber plunger is larger in diameter than the internal diameter of the barrel. Thus, to displace the rubber plunger when the injection product is to be dispensed from the syringe requires overcoming this pressing force of the rubber plunger. Moreover, not only does this pressing force provided by the rubber seal typically need to be overcome when initially moving the plunger, but this force also needs to continue to be overcome as the rubber plunger is displaced along the barrel during the dispensing of the injection product. The need for relatively elevated forces to advance the plunger in the syringe may increase the difficulty at which a user may administer the injection product from the syringe. This is particularly problematic for auto injection systems where the syringe is placed into the auto injection device and the plunger is advanced by a fixed spring. Accordingly, primary considerations concerning the use of a plunger in a pre-filled parenteral container include: (1) container closure integrity (“CCI”, defined below); and (2) plunger force (defined below) required to dispense syringe contents.
In practice, CCI and plunger force tend to be competing considerations. In other words, absent other factors, the tighter the fit between the plunger and the interior surface of the container to maintain adequate CCI, the greater the force necessary to advance the plunger in use. In the field of medical syringes, it is important to ensure that the plunger can move at a substantially constant speed and with a substantially constant force when advanced in the barrel. In addition, the force necessary to initiate plunger movement and then continue advancement of the plunger should be low enough to enable comfortable administration by a user.
Plunger force is essentially a function of the coefficients of friction of each of the contacting surfaces (i.e., the plunger surface and interior syringe wall surface) and the normal force exerted by the plunger against the interior wall of the syringe. The greater the respective coefficients of friction and the greater the normal force, the more force required to advance the plunger. Accordingly, efforts to improve plunger force should be directed to reducing friction and lowering normal force between contacting surfaces. However, such efforts should be tempered by the need to maintain adequate CCI, as discussed above.
To reduce friction and thus improve plunger force, lubrication may be applied to the plunger, the interior surface of the container, or both. Liquid or gel-like flowable lubricants, such as free silicone oil (e.g., polydimethylsiloxane or “PDMS”), may provide a desired level of lubrication to optimize plunger force. Optionally, use of free silicone oil to reduce plunger force, especially in small amounts, may in certain embodiments, be within the scope of the invention. However, for some applications, including preferred embodiments of the invention, use of large amounts of flowable lubricant is not desired. For example, a flowable lubricant can mix and interact with the drug product in a syringe, potentially degrading the drug or otherwise affecting its efficacy and/or safety. Such lubricants may in some cases be problematic if they are injected into the patient along with the drug product. In addition, flowable lubricants, when used with pre-filled syringes, may migrate away from the plunger over time, resulting in spots between the plunger and the interior surface of the container with little or no lubrication. This may cause a phenomenon known as “sticktion,” an industry term for the adhesion between the plunger and the barrel that needs to be overcome to break out the plunger and allow it to begin moving.
As an alternative (or in addition) to flowable lubricants, plungers may be made from materials having lubricious properties or include friction-reducing coatings or laminates on their exterior surfaces. Examples of such plungers include, for example: the i-COATING by TERUMO, which is disclosed in Canadian Patent No. 1,324,545, incorporated by reference herein in its entirety; W.L. Gore extended ETFE film on a rubber plunger; and the CZ plunger by WEST. While these commercially available plungers may complement a lubricated barrel to provide a desired level of plunger force, it has not been found that they provide desirable plunger force absent a lubricious coating or flowable lubricant on the barrel of coated or uncoated plastic parenteral containers.
As an alternative to free liquid lubricants, lubricious coatings may be applied to the interior wall of a container barrel. Lubricity coatings, e.g., according to methods disclosed in U.S. Pat. No. 7,985,188 (incorporated by reference herein in its entirety), are particularly well suited to provide a desired level of lubricity for plungers in parenteral containers. Such lubricity coatings are preferably applied using plasma enhanced chemical vapor deposition (“PECVD”) and may have one of the following atomic ratios, SiwOxCy or SiwNxCy, where w is 1, x is from about 0.5 to 2.4 and y is from about 0.6 to about 3. Such lubricity coatings may have a thickness between 10 and 500 nm. Advantages of such plasma coated lubricity layers may include lower migratory potential to move into the drug product or patient than liquid, sprayed or micron-coated silicones. It is contemplated that use of such lubricity coatings to reduce plunger force is within the broad scope of the invention. However, for some applications, including preferred applications of the invention, use of such lubricity coatings may not be optimal. For example, due to relatively low cross-link density, the lubricity layer may sometimes interact with the contents of the syringe, resulting in the presence of silicon ions being extracted from the lubricity layer into the syringe. In addition, application of a lubricity coating introduces an additional step in container manufacturing, thus increasing the complexity and cost of the manufacturing process.
Thus, there is a need for optimizing plunger force in a parenteral container while maintaining adequate CCI to prevent drug leakage, protect the drug product and attain sufficient product shelf life. In addition, there is a need to provide adequate lubricity to achieve a desired plunger force while minimizing extractables and interaction with the drug product held by the container. There is a further need to optimize these factors while reducing the manufacturing cost and complexity that may be associated with applying a discrete lubricity coating to a medical barrel.